For the past hundred years most clinical work and research in psychiatry
has proceeded under the assumption that schizophrenia and bipolar affective
disorder (or the corresponding earlier terms, such as dementia praecox and
manic–depressive illness) are distinct entities with separate underlying
disease processes and treatments. This so-called ‘Kraepelinian
dichotomy’ has pervaded Western psychiatry since Emil Kraepelin
(1919) ‘crystallised
dementia praecox and manic–depressive illness from an amorphous mass of
madness’ (Brockington & Leff,
1979), and remains enshrined in current classifications. However,
many individuals with severe psychiatric illness have both prominent mood and
psychotic symptoms – raising the possibility, indeed the likelihood,
that there is not a neat biological distinction between schizophrenia and
bipolar affective disorder. Genetic epidemiology has always been influential
in shaping and validating psychiatric nosology
(Robins & Guze, 1970). Now
molecular genetic studies are beginning to challenge and will soon, we
predict, overturn the traditional dichotomous view.

WHY HAS THE KRAEPELINIAN DICHOTOMY SURVIVED FOR SO LONG?

In the absence of ‘laboratory’ tests based on a solid
understanding of pathogenesis, the criteria available to psychiatry for
validating nosological categories have been restricted to clinical features,
outcome and family history (Robins &
Guze, 1970). These were the tools used by Kraepelin in formulating
his ideas and have been applied to research data in shaping the modern
operational classifications. One of the key scientific observations supporting
the Kraepelinian dichotomy was that the prototypical disorders tend to ‘
breed true’. Thus, a consistent finding has been a substantially
increased risk of schizophrenia but not bipolar disorder in the relatives of
probands with schizophrenia, and vice versa in corresponding studies of
bipolar disorder. It is also true that groups of individuals classified as
having typical schizophrenia can be discriminated from sets of individuals
classified as having typical bipolar disorder on the basis of clinical
features and outcome.

As well as having apparent empirical support, the Kraepelinian view holds
attractions for clinicians; it is conceptually simple and allows psychiatrists
to demonstrate diagnostic expertise by exercising judgement over an often
complex clinical picture and to reach a clear diagnosis. However, most
psychiatrists, although willing to make use of the advantages of the
dichotomy, are fully aware of its limitations, and this is mirrored in the
failure of nosologists to identify any ‘point of rarity’ between
the two disorders (Kendell,
1987). Cogent arguments for abandoning a categorical approach in
favour of a dimensional or continuous formulation have been advanced (e.g.
Crow, 1990). However, these
failed to gain widespread support, in part because of a lack of robust
scientific data, and possibly also because of the practical complexity of
applying dimensional classifications in clinical practice and research
settings.

WHY IS THIS DICHOTOMY NOW BEING CHALLENGED?

Evidence from genetic epidemiology has been gradually accumulating over the
past two decades that is inconsistent with the dichotomous view, and recent
molecular genetic findings seem set finally to overturn it. Key pieces of
evidence include the following.

Family studies point to the existence of a non-trivial degree of familial
coaggregation between schizophrenia and bipolar illness and between
schizo-affective disorders and both bipolar disorder and schizophrenia
(reviewed by Craddock et al,
2005).

A recent twin study – the only one that has used an analysis
unconstrained by the diagnostic hierarchy inherent in current classification
systems – demonstrated an overlap in the genetic susceptibility to mania
and schizophrenia (Cardno et al,
2002) and provided evidence that there are genes that confer
susceptibility across the Kraepelinian divide, to schizoaffective disorder and
to some cases of schizophrenia and bipolar disorder. This study also confirmed
the traditional notion that there are genes specific to the two prototypical
disorders.

Systematic, whole-genome linkage studies of schizophrenia and bipolar
disorder have implicated some chromosomal regions in common; this is
consistent with the presence of shared susceptibility genes
(Berrettini, 2003;
Craddock et al,
2005).

Most recently, and most convincingly, genes have been identified in which
variation appears to confer risk to both schizophrenia and bipolar disorder.
One example is the gene encoding d-amino acid oxidase activator
(formerly known as the G72/G30 locus) on chromosome 13q, one of the
regions implicated in genome scans of both disorders
(Craddock et al,
2005). This locus was originally reported as showing association
in schizophrenia in two independent samples. Subsequently association has been
reported in bipolar disorder in three independent samples. Another example is
the gene Disrupted in Schizophrenia 1 (DISC1). The gene, as the name
implies, is disrupted in a family in which both schizophrenia and bipolar
disorder co-segregate with a chromosomal translocation. Recent findings
suggest that schizophrenia, schizoaffective disorder and bipolar disorder
might be associated with polymorphisms in this gene
(Craddock et al,
2005).

WHAT ARE THE IMPLICATIONS FOR PSYCHIATRIC RESEARCH?

The Kraepelinian dichotomy has served academic psychiatry well. Indeed,
Kraepelinian diagnoses formed the basis of recent successes in genetics,
probably because their net effect is to simplify the genetic architecture of
the groups defined, albeit at the expense of excluding many cases. The
dichotomy also formed the basis of the operational diagnostic criteria that
brought a degree of rigour and reproducibility to psychiatric research.
However, there is a danger that it will now impede rather than aid progress.
The recent findings are compatible with a model of functional psychosis in
which susceptibility to a spectrum of clinical phenotypes is under the
influence of overlapping sets of genes which, together with environmental
factors, determine an individual’s expression of illness
(Fig. 1). Such a model,
although a better approximation than the dichotomous view, is itself only
crude. A more accurate model would probably be based in multidimensional space
because, in addition to the interface between bipolar disorder and
schizophrenia, there is genetic overlap between the functional psychoses and
major depressive disorder – and, indeed, other disorders – with
extension into subclinical (or normal) variation. It seems likely that sets of
overlapping genes will be identified that confer risks along different domains
of psychopathology, corresponding to the disruption of different brain
systems. Unravelling the biology underlying these overlaps will shed light on
the bewildering degree of ‘comorbidity’ observed across disorders
and the widespread non-specificity of treatments.

Possible relationship between susceptibility genes and the clinical picture
for disorders in the psychosis–bipolar spectrum. Recent genetic studies
suggest that there are genes specific to schizophrenia (S), genes specific to
bipolar disorder (B) and genes that confer risk to schizoaffective disorder,
schizophrenia and bipolar disorder (M). The combination of susceptibility
genes inherited by an individual, together with the environmental exposures,
determine the key clinical features of the illness, positioned on a spectrum
from prototypical schizophrenia at one end to prototypical bipolar disorder at
the other. Most cases lie somewhere in the central part of the spectrum.

This research agenda will best be served by adopting broader inclusion
criteria for the functional psychoses and by a combination of inductive and
hypothesis-driven approaches aimed at relating biological processes to
symptoms and syndromes defined at both clinical and endophenotypic levels.
This will require more detailed clinical analysis and the integration of data
across multiple domains such as genetics, environmental measures, brain
imaging and cognitive neurosciences. In order to achieve this, academic
psychiatry will need to scale up its ambitions and plan detailed
multidisciplinary, multicentre studies of large numbers of individuals with
psychosis. The creation of the Mental Health Research Network under the
auspices of the UK Clinical Research Collaboration offers a possible route
towards such studies in the UK.

Genetics will have an increasingly important role in all research aimed at
understanding the aetiology and pathogenesis of psychosis. As risk genes are
identified, so it will become possible to determine how genetic variation
relates to clinical variation across and outwith current diagnostic
categories, and to explore the relationship between variation in specific
susceptibility genes and the disruption of functional systems using techniques
such as imaging, psychological testing and neuropathological studies. Thus it
will become increasingly possible to seek correlations between psychopathology
and biological dysfunction. For example, genetic risk for prototypical
schizophrenia might in part be mediated by neurodevelopmental abnormalities
with associated structural brain changes and cognitive impairments
(Murray et al, 2004).
Risk of developing positive psychotic symptoms might be conferred by
genetically influenced abnormalities in dopamine and glutamate
neurotransmission, with abnormalities of synaptic function leading to abnormal
connectivity (Owen et al,
2005). These suggestions are illustrative, to indicate the
directions that research is likely to take in the coming decade and the power
of genetics to shape this agenda. Epidemiology, too, will benefit from
integration of the analysis of genetic and environmental risk factors and
exploration of the interplay between these two classes of aetiological
agent.

WHAT ARE THE IMPLICATIONS FOR CLINICAL PRACTICE?

In the coming years psychiatrists are likely to have at their disposal
simple and inexpensive tests to help identify the pathways involved in an
individual’s illness and there-by inform treatment decisions. Such tests
will not replace the clinical skills now used in diagnosis and management but
will be tools to aid these processes, much as lipid levels and blood enzyme
measurements aid cardiologists in management of cardio-vascular disease.

Changes in classification will accompany the improvements in understanding
of pathogenesis. These will require clinicians to embrace classifications that
are both more complex (more categories or, perhaps, dimensions) and also
simpler (because they map on to the biology of the illness more closely).
These developments have much to offer patients and the professional standing
of psychiatry. Most patients want to be given an unambiguous and accurate
diagnosis, but psychiatrists are understandably reluctant to be too dogmatic
in the early stages of psychotic illness, recognising that the cross-sectional
picture may change longitudinally – often frustrating patients, leading
to diagnostic revisions between categories and creating an impression that
psychiatrists are indecisive or incompetent. Moving to a spectrum concept (be
it with categories or dimensions) with recognition of overlapping pathogenetic
factors and varying expression (dependent upon both genetic risk and
environmental exposure) would allow a confident and clear diagnosis to be
offered (perhaps ‘psychosis-spectrum illness’ or ‘
mood–reality disorder’), with a clear explanation that some
specific tests and a period of observation will help to clarify the likely
course of illness and response to treatment. This would be greatly preferable
to the current situation and the inevitable consequences of damage to the
therapeutic alliance caused by diagnostic revisions.

The Kraepelinian dichotomy has been useful for a hundred years. Now it is
time to move on.